Lecture 10; Variability due to genetics

Question 1

Where can inherited differences in the disposition of drugs occur?

Answer 1

Absorption
Distribution
Metabolism
Excretion
Drug receptor targets

Question 2

What are drug metaboliser traits?

Answer 2

• Poor metabolisers
• Intermediate metabolisers
• Extensive metabolisers (Normal reference value)
• Ultra rapid metabolisers

Question 3

Write some notes on poor metaboliser trait:

Answer 3

• Inherited loss of function of a drug metabolising enzyme can result in no enzyme activity
• The poor metaboliser trait may lead to higher drug levels in the blood and this might result in increased risk of an adverse drug reaction compared with individuals with ‘normal’ metabolism
• Typically autosomal recessive (co-dominant)

Question 4

What is the function of omeprazole and what clears it?

Answer 4

Omeprazole

• Proton pump inhibitor (irreversible)
• H/K ATPase in the gastric parietal cells

CYP2C19 is major route of clearance

Question 5

What happens to people with two copies of null function CYP2C19 on omeprazole?

Answer 5

• They will be poor metabolisers of omeprazole
• Omeprazole concentrations will be elevated due to decreased renal clearance
• This can be detected by measuring metabolic ratio

Question 6

What is the metabolic ratio?

Answer 6

Drug/metabolite plasma concentration = metabolic ratio

High ratio = poor metaboliser
Low ratio = Extensive metaboliser

Question 7

What can happen with CYP2C19 genetic variants?

Answer 7

• Compound heterozygote but still homozygous for null function

I.e theres multiple gene variants that can lead to null function

Question 8

Is high omeprazole due to null function CYP2C19 likely to be toxic?

Answer 8

• Omeprazole has a wide therapeutic index
• Unlikely to be substantially toxic
• But a wide range of concentrations can be given to effectively suppress GA secretion

Question 9

What is clopidogrel?

Answer 9

Clopidogrel is used as antiplatlet therapy (combined with aspirin) after percutaneous coronary intervention (i.e stent) to minimise the risk of further ischeamia due to thrombosis

Prodrug that is bioactivated by CYP2C19

Question 10

What are the range of genetic variations that might influence clopidogrel?

Answer 10

• 17 carriers = Ultra rapid metabolisers

* 2 carriers = Intermediate or poor metabolisers

Question 11

Whats the risk for *17 and *2 carriers on clopidogrel:

Answer 11

• 17 = Increased risk of excessive bleeding, but, less chance of another CVE
• 2 = Increased risk of stent thrombosis (attenuated pharmacodynamic response) BUT no increased risk of another CVE

Question 12

What else can you do for people on clopidogrel who carry variant genes?

Answer 12

P2Y12 inhibitors: Prasugrel and ticagrelor, do not require metabolic conversion

• But higher bleeding risk than clopidogrel
• More effective at prevent ischeamic events

Question 13

Describe the major CYP2D6 gene variants:

Answer 13

Gene duplication (3 or 4 copies) = Ultra rapid metabolisers

SNP = *4 or *6 , no function alleles, Poor metabolisers

Question 14

Describe codeine metabolism:

Answer 14

• Analgesic properties of codeine require its conversion to morphine by CYP2D6
• Morphine and its metabolite; Morphine-6-glucuronide are active at its receptor.
• 50-70% codiene is metabolised to codiene-6-glucuronide and is eliminated

Question 15

Tramadol is also a CYP2D6 substrate, what will prescribing the standard dose to a poor metaboliser lead to?

Answer 15

Sub-therapeutic concentrations

Question 16

What is irinotecan (SN38)?

Answer 16

Anti-neoplastic effects of SN-38 is due to the potential inhibition of DNA topoisomerase
= Treatment of colorectal cancer

Narrow therapeutic index

Eliminated by hepatic glucornidation (catalysed by UGT1A1 enzyme)

Question 17

What are some variants in UTG1A1?

Answer 17

2BP insertion into UTG1A1 gene = UGT1A1*28

Decreases transcription and translation so produces 25% less enzyme and 50% Lower enzyme activity

The influence on clearance is predictable in manner

Question 18

What is the potential toxicity of UGT1A1*28?

Answer 18

Risk of severe toxicity - Grade 3-4 neutropenia

Question 19

Whats the further implications of UGT1A1 activity and irinotecan?

Answer 19

• Maximum dose was based on patients with unknown UGT1A1

- Thus people who are not poor metabolisers may be underdosed.

Question 20

What is azathioprine?

Answer 20

• Immunosuppressive medication
• Guanine analog that acts as an antimetabolite (interferes with de novo guanine synthesis for DNA and RNA)
• Leucocytes rely on de novo synthesis of purines (rather than salvage)
• It is a prodrug (Azathioprine -> 6-mercaptopurine)

Question 21

Describe the inherited deficiency in TMPT:

Answer 21

• Thiopurine methyl transferase (TMPT) is the major route of elimination of 6-MP
• Multiple non-functional alleles
• Increased risk of life
• Individuals who are poor metabolisers should receive a 10 fold lower starting dosage

Question 22

When is it important to consider the role of pharmacogenetic variability:

Answer 22

• Is metabolic clearance an important/major route of elimination of the drug from the body?
• Does the drug have one (or a limited number) of metabolic routes of elimination?
• Is the drug biotransformed into an active or inactive metabolite?
• Is there a narrow therapeutic index for the drug?

Question 23

Grab the blue table from the end of the slides and make sure you can complete it

Answer 23

Yes